SIRT1 deacetylates TopBP1 and modulates intra-S-phase checkpoint and DNA replication origin firing.

ABSTRACT: SIRT1, the mammalian homolog of yeast Sir2, is a founding member of a family of 7 protein and histone deacetylases that are involved in numerous biological functions. Previous studies revealed that SIRT1 deficiency results in genome instability, which eventually leads to cancer formation, yet the underlying mechanism is unclear. To investigate this, we conducted a proteomics study and found that SIRT1 interacted with many proteins involved in replication fork protection and origin firing. We demonstrated that loss of SIRT1 resulted in increased replication origin firing, asymmetric fork progression, defective intra-S-phase checkpoint, and chromosome damage. Mechanistically, SIRT1 deacetylates and affects the activity of TopBP1, which plays an essential role in DNA replication fork protecti

SUBMITTER: Wang RH 

PROVIDER: S-EPMC4261203 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature